Proton therapy is a favorable treatment modality for tumors with irregular shapes and near critical organs because of its ability to deliver highly conformal radiation dose distributions to the tumor target volume, with better sparing of surrounding normal tissues. Verification of the beam delivery within the patient is very important to ensure the proper functioning of treatment planning and delivery systems. Positron emission tomography (PET) is being investigated for the validation of beam delivery by imaging the activity distribution of positron-emitting radionuclides produced within the patient. The PET monitoring of proton therapy can be performed either during (in-beam) or after (off-line) the irradiation. In-beam monitoring is advantageous as both short-lived (such as 15O) and relatively long- lived nuclides (such as 11C and 13N) can be imaged with high sensitivity. However, it requires the integration of a dedicated PET imaging system into the proton therapy facility, usually a dual-head system since full-ring geometry is not feasible because of geometric constraints, and does not lead to full tomographical data. The technically less-demanding Off-line approach involves transporting the patient to a nearby commercial PET scanner (usually a full-ring system) outside the treatment room for imaging after the irradiation. However, usually there is a delay between irradiation and PET imaging so that short-lived nuclides, most importantly 15O, would have decayed. As a combination of these two scenarios, a full-ring PET scanner within the treatment room is very desirable so that the patient can be imaged immediately after irradiation. The in-room PET monitoring of proton therapy is possible with the recent availability of a mobile full-ring PET scanner, NeuroPET from PhotoDiagnostic Systems, at MGH. We will investigate the potentials of in-room PET monitoring/verification for proton therapy through a series of phantom and animal studies.